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F. Ulrich Hartl

Pascale Chenevier. Journal Club Jan. 28 2002. F. Ulrich Hartl. Protein folding in vivo. ?. Secondary structure. Tertiary structure. b strands. a helix. Luciferase from Protein Data Bank. Luciferase from Protein Data Bank. from Molecular Biology of the Cell , Alberts et al.

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F. Ulrich Hartl

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  1. Pascale Chenevier Journal Club Jan. 28 2002 F. Ulrich Hartl Protein folding in vivo ?

  2. Secondary structure Tertiary structure b strands a helix Luciferase from Protein Data Bank Luciferase from Protein Data Bank from Molecular Biology of the Cell, Alberts et al. Primary structure Firefly luciferase sequence MEDAKNIKKGPAPFYPLEDGTAGEQLHKAMKRYALVPG…

  3. Folding pathways?…

  4. Folding pathways in that environment ?? Folding in vivo requires a helping machinery : Molecules involved? Mechanisms? www.scripps.edu/pub/goodsell

  5. Hartl contributions : • identification of chaperone proteins Vainberg Cell 1998 • structure Siegert Cell 2000 • interaction with substrate, substrate specificityin vivo Houry Nature 1999 • function and mechanismin vivo Brinker Cell 2001 • cooperative folding machinery Siegers EMBO J 1999 • eukaryotes vs prokaryotes Frydman Nature SB 1999 Reviews Ellis Curr Opin Struc Biol 1999*** • Frydman Annu Rev Biochem 2001

  6. Chaperonin Hsp60/Hsp10 TRiC Chaperone Hsp70 Prefoldin GimC Chaperone Hsp40 Siegert Cell 2000 Chaperones and chaperonins (simplified overview)

  7. Statement 1 : folding information in primary structure Experiment : identification of chaperonin GroEL substrates Houry Nature 1999 Many associated proteins, no common sequence = no molecular recognition but preferred size and a-b domains

  8. + + + + + + + Statement 2 : The chaperone machinery does : 1) Enclose to prevent aggregation + Brinker Cell 2001

  9. + + + Statement 2 : The chaperone machinery does : 1) Enclose to prevent aggregation 2) Enhance folding rate Brinker Cell 2001

  10. GimC prefoldin Hsp60 chaperonin (bacterial) Statement 3 : Chaperones cooperate in compartmentalized pathways Vainberg Cell 1998 TRiC chaperonin actin

  11. Statement 4 : Co-translational folding helped eukaryotes to develop multidomain proteins DHFR Ras Netzer Nature 1997

  12. Some need chaperonin Most nascent chains interact with Hsp70 & Hsp40 Beginning of translation Integrated sequential pathway (prefoldin-chaperonin) Conclusion New chaperones still to discover? Coupling to translation? How is in vivo specificity achieved? Regulation and diseases due to misfolding? $one way folding process along translation?

  13. Folding compartment Denaturing compartment N C

  14. Next week Journal Club program… Onions as targeted biological vectors (my PhD thesis in short)

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